Asian and African lineage Zika viruses show differential replication and innate immune responses in human dendritic cells and macrophages

Abstract

Zika virus (ZIKV) infections in humans are considered to be mild or subclinical. However, during the recent epidemics in the Pacific Islands and the Americas, the infection was associated with Quillain-Barré syndrome and congenital infections with fetal brain abnormalities, including microcephaly. Thus, more detailed understanding of ZIKV-host cell interactions and regulation of innate immune responses by strains of differential evolutionary origin is required. Here, we characterized the infection and immune responses triggered by two epidemic Asian/American lineage viruses, including an isolate from fetal brains, and a historical, low passage 1947 African lineage virus in human monocyte-derived dendritic cells (DCs) and macrophages. The epidemic Asian/American ZIKV replicated well and induced relatively good antiviral responses in human DCs whereas the African strain replicated less efficiently and induced weaker immune responses. In macrophages both the African and Asian strains showed limited replication and relatively weak cytokine gene expression. Interestingly, in macrophages we observed host protein degradation, especially IRF3 and STAT2, at early phases of infection with both lineage viruses, suggesting an early proteasomal activation in phagocytic cells. Our data indicates that ZIKV evolution has led to significant phenotypic differences in the replication characteristics leading to differential regulation of host innate immune responses.

Recent African strains of Zika virus display higher transmissibility and fetal pathogenicity than Asian strains

“…ZIKV also has the potential to antagonize innate immune responses of the host, which may involve various ZIKV proteins 27,[63][64][65][66] . The mechanism by which the antagonistic effect is brought about may be shared by ZIKV strains from both lineages 66,67 , may be strain-or lineage dependent 39,68 , or has only been described for specific ZIKV strains 65 . However, immunocompromised mouse models are not suitable for comparing the ability of ZIKV strains to suppress or evade the host's immune system, which may additionally contribute to their epidemic potential.…”

Viral infection of human neurons triggers strain-specific differences in host neuronal and viral transcriptomes

“…Comparative genomic and transcriptomic approaches have been used to identify factors associated with disease pathogenesis in several viruses, and have helped elucidate virus straindependent differences in host responses that may impact disease outcome [53][54][55][56]. To date, few studies have simultaneously analyzed both the host and virus transcriptomes in an effort to identify potential virus strain-dependent differences in gene transcription that may differentially impact host cell processes.…”

An overview of Zika virus genotypes and their infectivity

“…However, Osterlund 53 observed differences in replication rates among these genotypes, although both showed great replication in human dendritic cells. Unlike the African genotype, viral replication in the Asian genotype is attenuated in human macrophages 53 . These findings suggest that the Asian-ZIKV genotype may use immunological cells as a viral reservoir.…”

“…According to Hou 26 , immunological cells did not demonstrate a difference in permissiveness between African- and Asian-ZIKV genotypes. However, Osterlund 53 observed differences in replication rates among these genotypes, although both showed great replication in human dendritic cells. Unlike the African genotype, viral replication in the Asian genotype is attenuated in human macrophages 53 .…”